Method for formulating organic compounds

ABSTRACT

The invention generally relates to a method of formylating organic compounds in a microreactor.

The present invention relates to a process for the formylation oforganic compounds.

The formylation of suitable organic compounds is a process which is veryfrequently carried out in the chemical industry and whose greatimportance is also reflected in numerous publications on this subject.

However, carrying out formylations on an industrial scale is accompaniedby safety problems and risks. Firstly, relatively large amounts ofhighly toxic chemical substances which themselves pose a considerablerisk to human beings and the environment are frequently used and,secondly, formylations frequently proceed very exothermically so thatthere is an increased risk of explosion when carrying out thesereactions on an industrial scale. Obtaining approval from theauthorities under the German Federal Pollution Control Law for theoperation of plants for the formylation of organic compounds on anindustrial scale is therefore associated with a considerable outlay.

It is therefore an object of the present invention to provide a processfor the formylation of organic compounds which avoids the abovementioneddisadvantages. This process should, in particular, be able to be carriedout in a simple, reproducible manner with increased safety for humanbeings and the environment and give good yields, and the reactionconditions should be very readily controllable.

This object is surprisingly achieved by the process of the invention forthe formylation of organic compounds, in which at least one organiccompound in liquid or dissolved form is mixed with at least oneformylation reagent in liquid or dissolved form in at least onemicroreactor, reacts during a residence time and the formylated organiccompound is, if desired, isolated from the reaction mixture.

For the purposes of the present invention, a formylation is a reactionin which an aldehyde group and/or a keto group is/are introduced into anorganic compound.

Advantageous embodiments of the process of the invention are describedin the subordinate claims.

According to the invention, individual organic compounds or mixtures ofat least two of these compounds can be reacted by the process claimed.Preference is given to reacting only one organic compound by the processof the invention.

For the purposes of the invention, a microreactor is a reactor having avolume of ≦1000 μl in which the liquids and/or solutions are intimatelymixed at least once. The volume of the microreactor is preferably ≦100μl, particularly preferably ≦50 μl.

The microreactor is preferably made of thin, interconnected siliconstructures.

The microreactor is preferably a miniaturized flow reactor, particularlypreferably a static micromixer. The microreactor is very particularlypreferably a static micromixer as described in the Patent Application WO96/30113, which is hereby incorporated by reference into the presentdisclosure. Such a micromixer has small channels in which liquids and/orchemical compounds present in solutions are mixed with one another bymeans of the kinetic energy of the flowing liquids and/or solutions.

The channels of the microreactor preferably have a diameter of from 10to 1000 μm, particularly preferably from 20 to 800 μm and veryparticularly preferably from 30 to 400 μm.

The liquids and/or solutions are preferably pumped into the microreactorso that they flow through the latter at a flow rate of from 0.01 μl/minto 100 ml/min, particularly preferably from 1 μl/min to 1 ml/min.

According to the invention, the microreactor can preferably be heatedand cooled.

The microreactor is, according to the invention, preferably connectedvia an output to at least one residence section, preferably a capillary,particularly preferably a heatable/coolable capillary. After they havebeen mixed in the microreactor, the liquids and/or solutions are passedthrough this residence section or capillary to increase their residencetime.

For the purposes of the invention, the residence time is the timebetween the mixing of the starting materials and the work-up of theresulting reaction solution for analysis or isolation of the desiredproduct(s).

The residence time necessary in the process of the invention depends onvarious parameters such as the temperature or the reactivity of thestarting materials. A person skilled in the art can match the residencetime to these parameters and thus achieve optimized reaction conditions.

The residence time of the reaction solution in the system employedcomprising at least one microreactor and, if desired, one residencesection can be set by choice of the flow rate of the liquids and/orsolutions used.

It is likewise preferred for the reaction mixture to be passed throughtwo or more microreactors connected in series. This increases theresidence time even in the case of an increased flow rate and results inthe components used in the formylation reaction being reacted so that anoptimum product yield of the desired formylated organic compound(s) isachieved.

In a further, preferred embodiment, the reaction mixture is passedthrough two or more microreactors connected in parallel so as toincrease the throughput.

In another preferred embodiment of the process of the invention, thenumber and arrangement of the channels is varied in one or moremicroreactor(s) so as to increase the residence time, so that an optimumyield of the desired formylated organic compound(s) is also achievedhere at an increased flow rate.

The residence time of the reaction solution in the microreactor or ifapplicable in the microreactor and the residence section is preferably≦15 hours, preferably ≦3 hours, particularly preferably ≦1 hour.

The process of the invention can be carried out within a very widetemperature range which is limited essentially by the temperaturestability of the materials used for the construction of themicroreactor, any residence section and further components such asconnections and seals and by the physical properties of the solutionsand/or liquids used. The process of the invention is preferably carriedout at a temperature of from −100 to +250° C., preferably from −78 to+150° C., particularly preferably from 0 to +100° C.

The process of the invention can be carried out either continuously orbatchwise. It is preferably carried out continuously.

To carry out the process of the invention for the formylation of organiccompounds, it is necessary for the formylation reaction to be carriedout, if possible, in a homogeneous liquid phase containing no solidparticles or only very small solid particles, since otherwise thechannels in the microreactors become blocked.

The course of the formylation reaction in the process of the inventioncan be followed by means of various analytical methods known to thoseskilled in the art and if necessary regulated. The course of thereaction is preferably followed chromatographically, particularlypreferably by high-pressure liquid chromatography, and regulated ifnecessary. The control of the reaction is significantly improvedcompared with known processes.

After the reaction, the formylated organic compound(s) is (are) isolatedif desired. The formylated organic compound(s) is (are) preferablyisolated from the reaction mixture by extraction.

As organic compounds, it is possible for all organic compounds known tothose skilled in the art as substrates for formylations to be used inthe process of the invention. The organic compounds are preferablyselected from among olefins, alkynes, aromatic compounds, heteroaromaticcompounds, transition metal complexes, CH-acid compounds, enamides andmixtures of at least two of these compounds.

As olefins, it is possible to use all olefins known to those skilled inthe art which are suitable as substrates for formulations. Theseencompass straight-chain, branched and cyclic olefins. Preference isgiven to using unsubstituted or substituted ethylene as olefin.

As alkynes, it is possible to use all alkynes known to those skilled inthe art which are suitable as substrates for formylations. Theseencompass straight-chain, branched and cyclic alkynes. Preference isgiven to using substituted acetylene as alkyne.

As aromatic compounds, it is possible to use all aromatic compoundsknown to those skilled in the art which are suitable as substrates forformulations. For the purposes of the invention, these include compoundsand/or derivatives which have a monocyclic and/or polycyclichomoaromatic framework or a corresponding substructure, e.g. in the formof substituents. As aromatic compound, which may be substituted orunsubstituted, preference is given to using azulene, indole, phenol, anaromatic amine or a mixture of at least two of these compounds.

As heteroaromatic compounds, it is possible to use all heteroaromaticcompounds known to those skilled in the art which are suitable assubstrates for formylations and have at least one heteroatom. For thepurposes of the invention, heteroaromatic compounds includeheteroaromatic compounds and/or their derivatives which have at leastone monocyclic and/or polycyclic heteroaromatic framework or acorresponding substructure, e.g. in the form of substituents. Theseheteroaromatic frameworks or substructures preferably include at leastone oxygen, nitrogen and/or sulfur atom. As heteroaromatic compounds,which may be substituted or unsubstituted, particularly preference isgiven to using furan, thiophene, pyrrole, benzofuran, benzothiophene,pyrazole, imidazole, thiazole, oxazole, pyrimidine, porphyrin,hydantoin, thiohydantoin, imidazolone, pyrazolone or a mixture of atleast two of these compounds.

As transition metal complexes, it is possible to use all transitionmetal complexes known to those skilled in the art which are suitable assubstrates or formylations. For the purposes of the invention,transition metal complexes include, inter alia, metallocene compounds,preferably ferrocene, and carbonyl compounds of the transition metals,preferably carbonyl compounds of iron, chromium or manganese andmixtures of at least two of these compounds.

As CH-acid compounds, it is possible to use all CH-acid compounds knownto those skilled in the art which are suitable as substrates forformylations and have at least one acid proton in the α positionrelative to a carbonyl group. As CH-acid compound, preference is givento using an enol, an enol ether, a β-keto compound, particularlypreferably pyrazole-3,5-dione, or a mixture of at least two of thesecompounds.

As enamides, it is possible to use all enamides known to those skilledin the art which are suitable as substrates for formylations. Asenamide, preference is given to using a vinylic formamide, particularlypreferably 3-dimethylaminopropenal.

Formylation reagents which can be used in the process of the inventionare all formylation reagents known to those skilled in the art which aresuitable for formylations and mixtures of at least two of thesereagents. Preference is given to using only one formulation reagent ineach case. For the purposes of the invention, formulation reagents alsoinclude formylation reagents formed in situ, i.e. formylation reagentswhich are formed immediately before or during the formylation reaction.

In a further, preferred embodiment of the invention, the formulationreagent used is an N,N-disubstituted formamide, an N-alkylformanilide,an N,N-disubstituted amide or a mixture of at least two of thesecompounds in the presence of an inorganic acid chloride, an inorganicester, an acid anhydride, an adduct of triphenylphosphine and bromine,cyanuric chloride, hexachlorocyclotriphosphazane or a mixture of atleast two of the abovementioned compounds.

As N,N-disubstituted formamide, preference is given to using anN-aryl-N-alkylformamide, particularly preferablyN-phenyl-N-methylformamide, an N,N-dialkyl formamide, particularlypreferably N,N-dimethylformamide, a vinylic N,N-dialkylformamide or amixture of at least two of these compounds.

As N-alkylformanilide, preference is given to using anN-methylformamide.

As N,N-disubstituted amide, preference is given to using anN,N-dialkylacetamide, particularly preferably N,N-dimethylacetamide, anN,N-dialkyl propionamide, particularly preferablyN,N-dimethylpropionamide, an N,N-dialkylbenzamide, preferablyN,N-dimethylbenzamide, or a mixture of at least two of these compounds.

As inorganic acid chloride, preference is given to using phosphorusoxychloride, thionyl chloride, phosgene, a phosgene substitute, inparticular diphosgene or triphosgene, pyrophosphoryl chloride, oxalylchloride, sulfuryl chloride, benzoyl bromide or a mixture of at leasttwo of these compounds.

As acid anhydride, preference is given to using trifluoromethanesulfonicanhydride.

As inorganic ester, preference is given to using a dialkyl sulfate,particularly preferably dimethyl sulfate.

The molar ratio of N,N-disubstituted formamide and/or N-alkylformanilideand/or N,N-disubstituted amide to inorganic acid chloride and/orinorganic ester and/or acid anhydride is preferably equimolar.Furthermore, the acid chloride and/or the inorganic ester and/or theacid anhydride is/are preferably present in a 2-fold to 10-fold molarexcess, particularly preferably in a 3-fold to 5-fold molar excess,based on the N,N-disubstituted formamide and/or the N-alkylformanilideand/or the N,N-disubstituted amide.

In a further, preferred embodiment of the process of the invention, theformylation reagent used is zinc(II) cyanide in the presence of a proticacid, preferably hydrochloric acid.

The molar ratio of organic compound to formylation reagent used in theprocess of the invention depends on the reactivity of the organiccompound used and the reactivity of the formylation reagent used. Theformylation reagent and the organic compound are preferably used in anequimolar ratio. In another preferred embodiment of the process of theinvention, the formylation reagent is used in a 2-fold to 20-fold molarexcess, particularly preferably in a 3-fold to 15-fold excess, veryparticularly preferably in a 4-fold to 10-fold excess, based on theorganic compound.

The selectivity of the reaction itself depends not only on theconcentration of the reagents used but also on a series of furtherparameters such as the temperature, the type of formylation reagent usedor the residence time. A person skilled in the art will be able to matchthe various parameters to the respective formylation so that the desiredformylation product(s) is (are) obtained.

It is important for the process of the invention that the organiccompounds used and the formylation reagents used are either themselvesliquid or are in dissolved form. If they are themselves liquid, theycan, if desired, also be used as solvents for further components of theformylation reaction. If the organic compounds or formylation reagentsused are not themselves in liquid form, they have to be dissolved in asuitable solvent before carrying out the process of the invention.Solvents used are preferably halogenated solvents, particularlypreferably dichloromethane, chloroform, 1,2-dichloroethane or1,1,2,2-tetrachloroethane, straight-chain, branched or cyclic paraffins,particularly preferably pentane, hexane, heptane, octane, cyclopentane,cyclohexane, cycloheptane or cyclooctane, or straight-chain, branched orcyclic ethers, particularly preferably diethyl ether, methyl tert-butylether, tetrahydrofuran or dioxane, aromatic solvents, particularlypreferably toluene, xylenes, ligroin or phenyl ether, N-containingsolvents, particularly preferably N,N-dimethylformamide orN-methylpyrrolidone, or mixtures of at least two of the abovementionedsolvents.

In the process of the invention, the danger to human beings and theenvironment due to loss of containment of chemicals is considerablyreduced and thus leads to increased safety when handling hazardoussubstances. Furthermore, the formylation of organic compounds by theprocess of the invention makes it possible for the reaction conditions,e.g. reaction time and reaction temperature, to be controlled betterthan is possible in the conventional processes. In addition, the risk ofexplosions in the case of very strongly exothermic formulations issignificantly reduced in the process of the invention. The temperaturecan be selected individually and kept constant in each volume element ofthe system. In the process of the invention, the formylation reactionsare very fast and can be regulated precisely. The formylated organiccompounds can thus be obtained in very good and reproducible yields.

It is also particularly advantageous that the process of the inventioncan be carried out continuously. As a result, it is faster and cheaperthan conventional processes and it is possible to prepare any amounts ofthe formylated organic compounds without a great outlay in terms ofinstrumentation.

The invention is illustrated below by means of an example. This exampleserves merely to illustrate the invention and does not restrict itsscope.

EXAMPLE Formylation of Indole to Give indole-3-carboxaldehyde

The formylation of indole by means of N,N-dimethylformamide in thepresence of phosphorus oxychloride was carried out in a staticmicromixer (Technische Universität Ilmenau, Fakultät Maschinenbau,Dr.-Ing. Norbert Schwesinger, Postfach 100565, D-98684, Ilmenau) havinga size of 40 mm×25 mm×1 mm and a total of 11 mixing stages each having avolume of 0.125 μl. The total pressure drop was about 1000 Pa. Thestatic micromixer was connected via an outlet and an Omnifitintermediate-pressure HPLC connector (Omnifit, Great Britain) to aTeflon capillary having an internal diameter of 0.49 mm and a length of1.0 m. The reaction was carried out at 0° C. and 25° C. The staticmicromixer and the Teflon capillary were for this purpose maintained atthe respective temperature in a thermostated double-walled vessel.

A 2 ml disposable syringe was filled with part of a solution of 0.78 ml(8.5 mmol) of phosphorus oxychloride and 20 ml of N,N-dimethylformamide,which simultaneously serves as solvent, and a further 2 ml disposablesyringe was filled with part of a solution of 1 g (8.5 mmol) of indolein 20 ml of N,N-dimethylformamide. The contents of both syringes weresubsequently transferred by means of a metering pump (Harvard ApparatusInc., Pump 22, South Natick, Mass., USA) into the static micromixer.Before carrying out the reaction, the test apparatus was calibrated todetermine the dependence of the residence time on the pump flow rate.The residence time was set to 1.88; 3.75; 7.5; 15 and 30 minutes. Thereactions were followed with the aid of a Merck Hitachi LaChrom HPLCinstrument. The ratio of starting material to product corresponding tothe respective reaction conditions and residence times was alsodetermined by means of HPLC on the abovementioned instrument.

1. A process for the formylation of at least one organic compound,comprising mixing the at least one organic compound in liquid ordissolved form with at least one formylation reagent in liquid ordissolved form in at least one microreactor, reacting during a residencetime and optionally isolating a formylated organic compound from thereaction mixture.
 2. A process according to claim 1, wherein themicroreactor is a miniaturized flow reactor.
 3. A process according toclaim 1, wherein the microreactor is a static micromixer.
 4. A processaccording to claim 1, wherein the microreactor is connected via anoutlet to a capillary, which can be heated and cooled.
 5. A processaccording to claim 1, wherein the volume of the microreactor is ≦about100 μl.
 6. A process according to claim 1, wherein the microreactor canbe heated and cooled.
 7. A process according to claim 1, wherein themicroreactor has channels having a diameter of about 10-about 1000 μm.8. A process according to claim 1, wherein the reaction mixture flowsthrough the microreactor at a flow rate of about 0.01 ml/min.-about 100ml/min.
 9. A process according to claim 1, wherein the residence time ofthe compounds used in the microreactor or in the microreactor and thecapillary is ≦about 15 hours.
 10. A process according to claim 1,wherein the process is carried out at a temperature of about −100-about+250° C.
 11. A process according to claim 1, further comprisingchromatography after the reaction.
 12. A process according to claim 1,wherein the formylated organic compound is isolated from the reactionmixture by extraction.
 13. A process according to claim 1, wherein theformylation reagent is an N,N-disubstituted formamide, anN-alkylformanilide, an N,N-disubstituted amide or a mixture of at leasttwo of these compounds in the presence of an inorganic acid chloride, aninorganic ester, an acid anhydride, an adduct of triphenylphosphine andbromine, cyanuric chloride, hexachlorocyclophosphazane or a mixture ofat least two of these compounds.
 14. A process according to claim 13,wherein the formulation reagent is at least one N,N-disubstitutedformamide, which is an N-aryl-N-alkylformamide, an N,N-dialkylformamide,a vinylic N,N-dialkylformamide or a mixture of at least two of thesecompounds.
 15. A process according to claim 13, wherein the formylationreagent is the N-alkylformanilide, which in turn is N-methylformamide.16. A process according to claim 13, wherein the formylation reagent isat least one N,N-disubstituted amide, which in turn is anN,N-dialkylacetamide, an N,N-dialkyl propionamide, anN,N-dialkylbenzamide, or a mixture of at least two of these compounds.17. A process according to claim 13, wherein the formylation reagent isat least one inorganic acid chloride, which in turn is phosphorusoxychloride, thionyl chloride, phosgene, a phosgene substitute,pyrophosphoryl chloride, oxalyl chloride, sulfuryl chloride, benzoylchloride or a mixture of at least two of these acid chlorides.
 18. Aprocess according to claim 13, wherein the formylation reagent is theinorganic ester, which in turn is a dialkyl sulfate.
 19. A processaccording to claim 13, wherein the formylation reagent is the acidanhydride of trifluoromethanesulfonic anhydride.
 20. A process accordingto claim 13, wherein the molar ratio of the N,N-disubstituted formamideand/or the N-alkylformanilide and/or the N N-disubstituted amide toinorganic acid chloride and/or the inorganic ester and/or the acidanhydride is equimolar, or the inorganic acid chloride and/or theinorganic ester and/or the acid anhydride is/are used in a about2-fold-about 10-fold polar excess, based on the N,N-disubstitutedformamide and/or the N-alkylformanilide and/or the N,N-disubstitutedamide.
 21. A process according to claim 1, wherein the formylationreagent is zinc(II) cyanide in the presence of a protic acid.
 22. Aprocess according to claim 1, wherein the at least one organic compoundused is an olefin, an alkyne, an aromatic compound, a heteroaromaticcompound, a transition metal complex, a CH-acid compound, an enamide ora mixture of at least two of these compounds.
 23. A process according toclaim 22, wherein the at least one organic compound is the olefin, whichis an unsubstituted or a substituted ethylene.
 24. A process accordingto claim 22, wherein the at least one organic compound is the alkyne ofan unsubstituted or a substituted acetylene.
 25. A process according toclaim 22, wherein the at least one organic compound is the aromaticcompound, optionally substituted, of an azulene, indole, phenol, anaromatic amine or a mixture of at least two of these compounds.
 26. Aprocess according to claim 22, wherein the at least one organic compoundis the transition metal complex of a metallocene, a carbonyl compound ofa transition metal, or a mixture of at least two of these compounds. 27.A process according to claim 22, wherein the at least one organiccompound is the heteroaromatic compound, optionally substituted, of afuran, thiophene, pyrrole, benzofuran, benzothiophene, pyrazole,imidazole, thiazole, oxazole, pyrimidine, porphyrin, hydantoin,thiohydantoin, imidazolone, pyrazolone or a mixture of at least two ofthese compounds.
 28. A process according to claim 22, wherein the atleast one organic compound is the CH-acid compound of an enol, an enolether or a β-keto compound, or a mixture of at least two of thesecompounds.
 29. A process according to claim 22, wherein the at least oneorganic compound is a vinylic formamide.
 30. A process according toclaim 1, wherein the molar ratio of the organic compound to theformylation reagent is equimolar, or the formylation reagent is used ina about 2-fold-about 20-fold molar excess, based on the organiccompound.
 31. A process according to claim 26, wherein the transitionmetal complex is a metallocene, which in turn is a ferrocene.
 32. Aprocess according to claim 26, wherein the transition metal complex isthe carbonyl compound of the transition metal, which in turn is an iron,chromium or a manganese carbonyl compound.
 33. A process according toclaim 1, wherein the volume of the microreactor is ≦about 50 μl.
 34. Aprocess according to claim 1, wherein the microreactor has channelshaving a diameter of about 20-about 800 μl.
 35. A process according toclaim 1, wherein the microreactor has channels having a diameter ofabout 30-about 400 μl.
 36. A process according to claim 1, wherein thereaction mixture flows through the microreactor at a flow rate of about1 μl/min-about 1 ml/min.
 37. A process according to claim 1, wherein theresidence time of the compounds used in the microreactor or in themicroreactor and the capillary is ≦about 3 hours.
 38. A processaccording to claim 1, wherein the residence time of the compounds usedin the microreactor or in the microreactor and the capillary is ≦about 1hour.
 39. A process according to claim 1, wherein the process is carriedout at a temperature of about −78-about +150° C.
 40. A process accordingto claim 1, wherein the process is carried out at a temperature of about0−+about 100° C.
 41. A process according to claim 13, wherein theformylation reagent is at least one N,N-disubstituted amide, which inturn is N,N-dimethylacetamide, N,N-dimethylpropionamide,N,N-dimethylbenzamide, or a mixture of at least two of these compounds.42. A process according to claim 17, wherein the phosgene substitute isdiphosgene or triphosgene.
 43. A process according to claim 20, whereinthe inorganic acid chloride and/or inorganic ester and/or acid anhydrideis/are used in about 3-fold-about a 5-fold molar excess, based on theN,N-disubstituted formamide and/or the N-alkyl formanilide and/or theN,N-disubstituted amide.
 44. A process according to claim 1, wherein themolar ratio of the organic compound to formylation reagent is equimolar,or the formylation reagent is used in about a 3-fold-about a 15-foldmolar excess based on the organic compound.
 45. A process according toclaim 1, wherein the molar ratio of the organic compound to formylationreagent is equimolar, or the formylation reagent is used in about a4-fold-about a 10-fold molar excess based on the organic compound.
 46. Aprocess according to claim 1, wherein the at least one organic compoundis indole.
 47. A process according to claim 1, wherein the at least oneorganic compound is indole and the formylation reagent isN,N-dimethylformamide in the presence of a phosphorus oxychloride.
 48. Aprocess according to claim 18, wherein the dialkyl sulfate is dimethylsulfate.
 49. A process according to claim 13, wherein the formylationreagent is an N-phenyl-N-methylformamide, or an N,N-dimethylformamide.50. A process according to claim 11, wherein the chromatography is ahigh-pressure liquid chromatography, and the reaction is regulated.